1. Field Of The Invention
This invention relates to a new 2-aryl substituted N-acetyl tryptamines and the use of such new compounds to treat psychiatric or other disorders in a human or other mammals related to melatonin function or influenced by melatonin and circadian rhythms.
2. Background of the Art
Melatonin, 5-methoxy-N-acetyl tryptamine is produced in the pineal gland. The synthesis and secretion of melatonin exhibit a circadian rhythm that changes with the seasons and with age, e.g., pubescence and senescence. The rhythm appears to be the result of both endogenous mechanisms and environmental cues, most notably the exposure of mammals to light, which inhibits melatonin synthesis and secretion. Melatonin is thought to be the hormonal mediator of photoperiodic changes. Evidence suggests that melatonin is involved in the regulation of circadian rhythms and a variety of neural and endocrine functions.
Numerous neuroendocrine functions have been attributed to the hormone melatonin with a main site of action at the level of the hypothalamic-pituitary axis. [See Minneman and Wurtman, Life Science, 17:1189-1200 (1975), and Cardinali, et al., Endocrinology, 105:437-441 (1979)]. However, the lack of suitable in vitro preparation has hindered the characterization of the melatonin receptor and the screening of potential melatonin receptor antagonist. In the past, melatonin responses have been studied on amphibian dermal melanocytes, using in vivo [Quay and Bagnara, Arch. Int. Pharmacodyn. Ther., 150:137-143 (1964)], or in vitro methods [Heward and Hadley, Life Sci., 17:1167-1168 (1975). Melatonin at picomolar concentrations has been found to inhibit the calcium-dependent release of .sup.3 H dopamine from the rabbit retina in vitro [Dubocovich, Nature 306:782-784 (1983)]. This assay appears to be more sensitive and a better quantitative technique to determine the potency of melatonin and related compounds than the photometric measurement of reflectance in amphibian dermal melanocytes after exposure to these compounds (Quay and Bagnara, supra). Dubocovich [Journal of Pharmacology and Experimental Therapeutics, 234:395-401 (1985)] describes the structure-activity relationship of melatonin and related indoles on the calcium-dependent release of .sup.3 H dopamine and the properties of N-acetyl tryptamine (Heward and Hadley, supra) as a melatonin receptor antagonist using the rabbit or chicken retina. By the use of this assay, 2-aryl substituted N-acetyl tryptamine compounds (disclosed in applicant's U.S. patent applications Ser. Nos. 07/086,290 and 07/086,062, both filed Aug. 17, 1987, and hereby incorporated by reference in their entirety) have been defined as melatonin receptor antagonists. The present invention relates to the use of melatonin receptor antagonist as defined by the Dubocovich assay for antidepressant agents.
Typically, melatonin has been implicated in a number of human disorders, particularly those relating to chronobiologic abnormalities. Researchers have suggested administering melatonin to alleviate or prevent disturbances in circadian rhythms caused by the rapid crossing of time zones, e.g., jet lag, or changes in work shifts from night to day. See European Patent Application 0 126 630, by Short, et al.
It has been proposed that melatonin mediates the effects of shortening days on the winter depressive symptoms of seasonal affective disorder (SAD) and that the symptoms of SAD result from secretion of melatonin, either in some abnormal way or in a population which is abnormally sensitive to its effects. See Rosenthal, et al., J. Neural Transm. [suppl] 21:258-267 (1986). Bright light can suppress nighttime melatonin production in humans, but ordinary indoor light does not have this effect. As stated by Lewy et al., Psychophormecal. Bull. 20, 561-565 (1984), these findings suggest that bright artificial light may be used to manipulate human biological rhythms. Lewy, in Science, Vol. 235, at pp. 352-354 (1987) uses bright light to shift the peak of nighttime melatonin production in humans and has shown that this treatment reverses the depressive symptoms of patients with SAD. Bright light has also been used to treat chronobiologic sleep disorders.
Specifically, chronobiological sleep and mood disorders have been effectively treated with bright light which appears to shift circadian rhythms (e.g., that of melatonin). A melatonin receptor antagonist, by altering the effect of melatonin at target sites (e.g., receptors), will act in the same way as bright light. It follows that if bright light exerts an antidepressant effect or is therapeutic for sleep disorders, melatonin receptor antagonists administered instead of light will have the same therapeutic effect.
Melatonin analogues have been studied for their effects on the reproductive system, specifically antigonadal activity and inhibition of release of luteinizing hormone (LH). See Flaugh et al., Journal of Medicinal Chemistry, Vol. 22 at pp. 63-69.
Frohn et al., Life Sciences, Vol. 27, pp. 2043-2046, Pergamon Press, and Clemens et al., J. Neural Transm. [suppl] 21:451-459 (1986), disclose melatonin analogues wherein the activity of such analogues is related to structure. Analogues with improved metabolic stability are disclosed.